Naphthofuranone Derivatives as Specific Inhibitors of Thymidylate Synthases

Abstract

Synthetic compounds of 1,2-naphthalein moelcules (I) having specific inhibitory properties of the enzymatic activity of thymidylate synthases of bacterial species, their preparation, their pharmaceutical composition and use in the treatment and prophylaxis of infectious pathologies are disclosed.

1 . A compound of the general formula (I) 
     
       
         
         
             
             
         
       
     
     Wherein: A and B stand for C═O, a formula G molecular fragment 
     
       
         
         
             
             
         
       
     
     Wherein: R, R 1  and R 2  each represent:
 (a) hydrogen; 
 (b) C 1-12  alkyl linear or branched chain, which can contain from 1 to 3 double or triple bonds and, if needed, can be substituted by/with one, two or three substituents such as fluorine, chlorine, bromine, iodine, NO, NR; wherein R may represent hydrogen, C 1-12  alkyl. 
 (c) halogen, including fluorine, chlorine, bromine, iodine, 
 (d) NO, NR, SH, SO HR groups, wherein R is the same as above defined, with the proviso that when A is C═O, so B is G, and when A is G, as a consequence B is C═O; in consideration of the fact that the hereof general formula compound is specified, if needed, through a regioisomeric (Iα) 
 
     or (Iβ) form: 
     
       
         
         
             
             
         
       
     
   
   
       2 . A method of preparation of a compound of the general formula (I) according to  claim 1 ; said preparation method providing a reaction between 1,2-napthalic anhydride and a phenol compound, having the following formula; 
     
       
         
         
             
             
         
       
     
     separating the resulting mixture of regioisomeric compounds of Formula I into the single regioisomeric compounds of formula (Iα) and (Iβ); further converting, if desired, a regioisomeric compound of Formula (Iα) in another compound of formula (Iα) or a regioisomeric compound of formula (Iβ) in another compound of formula (Iβ). 
   
   
       3 . A compound of formula (I) according to  claim 1 , where said compound is: 
     3,3-Bis-(4-hydroxyphenyl)-3H-naphtho[1,2-c]furan-1-one (Compound 1) 
     3,3-Bis-(4-hydroxy-5-isopropyl-2-metilphenyl)-3H-naphtho[1,2-c]furan-1-one (Compound 2). 
     3,3-Bis-(3-iodo-4-hydroxyphenyl)-3H-naphtho[1,2-c]furan-1-one (Compound 3). 
     3,3-Bis-(3-bromo-4-hydroxyphenyl)-3H-naphtho[1,2-c]furan-1-one (Compound 4). 
     3,3-Bis-(3,5-bromo-4-hydroxyphenyl)-3H-naphtho[1,2-c]furan-1-one (Compound 5). 
     3,3-Bis-(4-hydroxyphenyl)-1H-naphtho[1,2-c]furan-3-one (Compound 6) 
     3,3-Bis-(3-chloro-4-hydroxyphenyl)-1H-naphtho[1,2-c]furan-3-one (Compound 7) 
     3,3-Bis-(3-fluoro-4-hydroxyphenyl)-1H-naphtho[1,2-c]furan-3-one (Compound 8). 
   
   
       4 . Use of a compound in accordance with  claim 1  in order to inhibit particularly the bacterial thymidylate synthase. 
   
   
       5 . Use of an efficient quantity of a compound in accordance with  claim 1  in order to prepare a medicament for the treatment, the prevention or the prophylaxis of an infectious pathology caused and/or supported by bacteria; said treatment being executed or simplified by inhibiting thymidylate synthase activity of pathogenous bacteria, including, (but not restricting to),  Enterococcuc faecalis, Staphilococcus aureus, Criptococcus neoformans, Pneumocistis carini Listeria monocytogenes,  fungi, parasites in a mammal, particularly human beings. 
   
   
       6 . A pharmaceutical composition including a quantity of a compound that will be effective for the treatment, the prevention or the prophylaxis of an infectious pathology in accordance with  claim 5 , and a pharmaceutically acceptable carrier.